The approximately 1.3 million new cases of nonmelanoma skin cancers diagnosed each year in the USA have a tremendous impact on public health and healthcare expenditures. Therefore, safe and effective chemopreventive strategies are urgently needed. Overexposure to solar ultraviolet (UV) radiation is a primary risk factor and that UV-induced immunosuppression plays a critical role in skin carcinogenesis. It is well established that UV irradiation induces inflammatory mediators, impairs the function of dendritic cells (DC) and effector T cells and induces suppressor T cells. UV-induced epigenetic modifications, such as DNA hypermethylation, seem to play an important role in photodamage of the skin. A model is now emerging that suggests that epigenetic modifications, including DNA hypermethylation, are induced by UVB-induced inflammatory mediators, such as cyclooxygenase-2 (COX-2)/prostaglandin E2, and act as a mechanistic link between the inflammatory mediators and compromised DC function. We have demonstrated that topical administration of honokiol, a phytochemical from the Magnolia plant, prevents both photocarcinogenesis and UVB-induced immunosuppression in mice. Our preliminary data further indicate that honokiol can correct or inhibit DNA hypermethylation in UV-exposed dendritic cells and that this restores dendritic cell-mediated activities including stimulation of cells. We propose to test the innovative hypothesis that inhibition of UVB-induced DNA hypermethylation by honokiol is critical for its chemopreventive effects on UV- induced immunosuppression. We propose three inter-related Specific Aims to test the hypothesis in a mouse model: (1) Determine whether honokiol-induced inhibition of UV-induced immunosuppression occurs through DNA demethylation in UV-exposed skin and whether the inflammatory mediators play a role in this; (2) Determine whether honokiol inhibits the development of UV-induced tolerogenic DCs and whether this is mediated through inhibition of DNA hypermethylation; and (3) Determine whether honokiol inhibition of UV- induced immunosuppression occurs through enhancement of T cell activation and whether this is mediated through inhibition of DNA hypermethylation. A combination of approaches will be utilized to verify the results including the use of COX-2 deficient mice. Innovation: The proposed studies will: (1) Identify the mechanisms by which topical or oral administration of honokiol acts to correct UV-induced immunosuppression and prevent photocarcinogenesis, thereby providing data needed for further clinical development of this promising phytochemical; and (2) The data generated will provide critical insights into the mechanisms that elicit UVB- induced DNA hypermethylation in DC and establish whether targeting of these mechanisms is sufficient to prevent UVB-induced immunosuppression. Impact: The development of new early intervention strategies using honokiol may help to reduce the risk of skin cancer in humans, as the risk of skin cancer is a major public health concern.